Neonatal Research

Making the milk thicker, in order to make it harder to reflux, has a long history in the treatment of GE reflux, or spitting-up babies. As I mentioned in a previous post there are some thickeners that have been associated with NEC, specifically xanthan gum.

In general, in good studies, the effects of thickeners have been modest or absent, in terms of reducing reflux. One group has previously studied Gaviscon, which is an alginate that sort of clots in the stomach, so reducing reflux. They showed that it did reduce reflux, but did not reduce apnea.

The most recent study from that same group looked at the effects of another agent, amylopectin. They again showed in a small cross-over RCT that thickening reduced reflux (in this case acid reflux but not non-acid reflux) but did not reduce apnea, the most parsimonious explanation for this is that reflux has nothing to do with apnea.

That is exactly the interpretation that Christian Poets puts on the data in his accompanying editorial .

In fact Corvaglia and colleagues are the only group that has consistently shown a relationship between reflux and apnea. If you look at their data closely, it appears that the apneas that they find after feeds more than between feeds, and that they seem to show are associated with reflux on Multi-luminal impedance monitoring, are short apneas of 5 seconds or more. It does not appear that pathologic apneas, with associated hypoxia and bradycardia are associated, even in their studies. Maybe this is the difference to other investigators, and the reason why those others, who only looked at longer, pathological apneas, have not found any association.

Yet another small RCT of probiotics. This time 150 infants less than 1500 grams birth weight in an NICU in Mexico were randomized to a mixture of 4 different Lactobacilli and Bifidobacterium infantis or control. There was a reduction in NEC stage 2 or greater (6/75 vs 12/75) of about the same magnitude as all the other trials. They also had lower mortality, and no adverse effects.

Here is the funnel plot with the new new study added. I can only say it again, its time we stopped doing placebo controlled RCTs and focused on finding the best preparation, and the optimal dose and timing. RCTs in women at risk of preterm delivery are also a good idea.

Abbas W, Attia NI, Hassanein SM: Two-stage single-volume exchange transfusion in severe hemolytic disease of the newborn. The journal of maternal-fetal & neonatal medicine. 2012, 25(7):1080-1083. In this randomized clinical trial the authors did 104 exchange transfusions, they randomized the infants to either have a standard double volume exchange or the experimental technique which was to wait for 3 hours between the 2 single volume exchanges. The immediate effects were identical with a good lowering of the bilirubin, but the intervention group had much less rebound after the exchange was finished, to about 210 rather than 290. Unfortunately the report doesn’t clearly state when the rebound levels were taken, or even if they were measured at the same time in each group, but it looks like they were taken at 3 hours post exchange according to one of the tables. Also fewer of the intervention group needed as 2nd exchange.

In my hospital to do a study with 104 exchanges would take about 104 years, which means 2 things to me, 1. to improve techniques and treatments for severe jaundice we have to rely on studies from countries without well established anti-rhesus IgG programs. 2. Those countries need to develop anti-rhesus IgG programs!

Berry J, Griffiths M, Westcott C: A double-blind, randomized, controlled trial of tongue-tie division and its immediate effect on breastfeeding. Breastfeed Med 2012, 7(3):189-193. This is one of the oldest debates in care of the newborn, does tongue-tie affect feeding, and does cutting the tie improve feeding. This was an RCT in breastfed babies. The observer scoring the rbeastfeeding adn the mother were masked as to whether an actual frenulotomy had been performed or not, the baby was taken away from the mother, either a real or sham frenulotomy was performed and the babe was then returned to the mother with a piece of gauze under the tongue. There were 30 babies in each group, and the primary outcome was improvement in breast feeding. The tongue tie group had 78% of the babies feeding improved after the procedure and the controls 48%.

there are a couple of issues with this study, 1 I don’t know if you should really call this double blind as the baby probably knew it had the procedure! and 2. seriously this time, there was no anesthetic or analgesic used. I think that is appalling. there is no reason why a little topical anesthetic or at least some analgesia, such as sucrose, could not be given. The authors state that there is a NICE guidance, which they say requested further studies to provide evidence ‘that division of tongue-tie without an anesthetic in infants is safe,  successful, and acceptable to parents’. In fact the guidance requests no such thing. The NICE review notes that the procedure is usually performed without anesthesia, and suggests further studies, but does not suggest further studies without anesthesia, it is in fact silent on the issue as far as a recommendation is performed. Also the study was actually performed in 2003 and 2004, so they can’t use the NICE guidance published in 2005 as justification for not giving analgesia. Some infants do sleep through the procedure, but others cry and do demonstrate pain responses.

It certainly now looks like division of a tongue tie improves poor breast feeding, as well as reducing nipple pain ( as shown previously) so a referral to someone who has been trained to do it seems appropriate, but find someone who gives an anesthetic, or at least some analgesic.

Autrata R, Krejcirova I, Senkova K, Holousova M, Dolezel Z, Borek I: Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone i and posterior zone ii. European journal of ophthalmology 2012, 22(5):687-694. This multi-center RCT of retinopathy treatment enrolled a very high risk group of babies. Stage 3 with plus in zone 1 or poterior zone 2. They compared laser plus pegaptanib, a VEGF-165 inhibitor. Apparently this agent is more selective than the one that was used in the BEAT-ROP trial (called bevacizumab) it is an RNA aptamer whatever that means! The biggest other difference between this trial and BEAT-ROP is that all the babies in both groups got laser therapy. The conventional treatment group received laser therapy ‘combined with cryotherapy’ but the cryo is never described, we don’t know who got cryo for what indications. The authors state that they followed the ETROP recommendations, but those recommendations don’t suggest combined laser and cryotherapy, so I don’t undestand this at all.

One of the major advantages of anti-VEGF treatment as far as I can see is avoidance of laser. Laser therapy injures the peripheral retina, requires a very sedated baby, often one who has to be re-intubated for the procedure, and as many of the babies also have BPD, avoiding re-intubation is a big advantage. The primary outcome of this trial was recurrence of stage 3+ disease, and there was significantly less recurrence after pegaptanib than after conventional therapy, 15% versus 50%.

Pasquali SK, Ohye RG, Lu M, Kaltman J, Caldarone CA, Pizarro C, Dunbar-Masterson C, Gaynor JW, Jacobs JP, Kaza AK et al: Variation in perioperative care across centers for infants undergoing the norwood procedure. J Thorac Cardiovasc Surg 2012, 144(4):915-921.
Ohye RG, Schonbeck JV, Eghtesady P, Laussen PC, Pizarro C, Shrader P, Frank DU, Graham EM, Hill KD, Jacobs JP et al: Cause, timing, and location of death in the single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):907-914.
Tabbutt S, Ghanayem N, Ravishankar C, Sleeper LA, Cooper DS, Frank DU, Lu M, Pizarro C, Frommelt P, Goldberg CS et al: Risk factors for hospital morbidity and mortality after the norwood procedure: A report from the pediatric heart network single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):882-895.
Ghanayem NS, Allen KR, Tabbutt S, Atz AM, Clabby ML, Cooper DS, Eghtesady P, Frommelt PC, Gruber PJ, Hill KD et al: Interstage mortality after the norwood procedure: Results of the multicenter single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):896-906.
These publications are all from the Single Ventricle Reconstruction Trial, which was a surgical RCT of about 550 infants with hypoplastic left heart syndrome randomized to different forms of the Norwood procedure. These secondary analyses show that there are enormous variations in many different aspects of perioperative care, and that many babies die between different stages of the surgical repair. Bravo to the collaborators for doing a very difficult trial. The next stage will be to do more trials to find out which of these differences in care really have an impact on clinical outcomes.

Moon C, Lagercrantz H, Kuhl PK: Language experienced in utero affects vowel perception after birth: A two-country study. Acta Paediatrica 2012. This is neat, the researchers played recordings of different vowel sounds to Swedish and American babies who were just about 1 day old, sucking frequency changed when the vowel sounds that were from their own region were played to them compared to the non-native sounds. Looks like the vowel sounds the fetus heard before birth affect cerebral development some way, so that different vowel sounds after birth elicit different responses to those they have already heard.

Klinger G, Sokolover N, Boyko V, Sirota L, Lerner-Geva L, Reichman B, in collaboration with the Israel Neonatal N: Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-low-birthweight infants. Am J Obstet Gynecol 2012. An epidemiologic analysis of antecedents of BPD in a cohort from Israel. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86).

Carey JC: Perspectives on the care and management of infants with trisomy 18 and trisomy 13: Striving for balance. Current Opinion in Pediatrics 2012, 24(6):672-678. A very thoughtful review and opinion article about how to care for families with an infant who has trisomy 18 or 13.

Cheong JL, Coleman L, Hunt RW, Lee KJ, Doyle LW, Inder TE, Jacobs SE, Infant Cooling Evaluation C: Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: Substudy of a randomized trial. Arch Pediatr Adolesc Med 2012, 166(7):634-640. MRI is fairly predictive of death or major disability at 2 years of age. PPV for the abnomalities of white or grey matter that they investigated were mostly around 85%, so only 15% were survivors without major disability (false positives). There were a lot of false negatives though, around 40% of the babies with a normal MRI score in each category still had either death or major disability. Disability included Bayley Scores more than 2SD below the mean, which I have criticized before; a low Bayley score is not a disability. But in infants with HIE it does seem more predictive of future intellectual impairment than it is among ex-preterm infants.

Ferraretti AP, Goossens V, de Mouzon J, Bhattacharya S, Castilla JA, Korsak V, Kupka M, Nygren KG, Nyboe Andersen A, IVF-monitoring TE et al: Assisted reproductive technology in europe, 2008: Results generated from european registers by eshre. Human Reproduction 2012, 27(9):2571-2584. If you saw my other post earlier, this is the source of the European data, from 2008 of ART success and complication rates.

Sarajuuri A, Jokinen E, Mildh L, Tujulin A-M, Mattila I, Valanne L, Lönnqvist T: Neurodevelopmental burden at age 5 years in patients with univentricular heart. Pediatrics 2012. This study followed infants with univentricular lesions, both hypoplastic left heart syndrome and other single ventricles. about a quarter had major neurodevelopmental dysfunction in both groups, full-scale IQ was lower in patients with HLHS and with single ventricle than controls. One thing I found very interesting were the actual numbers, median IQ was 97 for HLHS, 112 for single ventricle and 121 for the controls. 121! I guess the Finns are very smart people.

Shin M, Kucik JE, Siffel C, Lu C, Shaw GM, Canfield MA, Correa A: Improved survival among children with spina bifida in the united states. The Journal of Pediatrics 2012, 161(6):1132-1137.e1133. Survival to one year of age of infants born with spina bifida continues to improve in the USA, up to 93% overall, there are unexplained ethnic differences in survival (it is over 96% in white families), and survival is lower if the baby also has a serious congenital heart disease, or a high lesion, cervical or thoracic, or if born with very low birth weight.

Lee SK, Ye XY, Singhal N, De La Rue S, Lodha A, Shah PS, for The Canadian Neonatal N: Higher altitude and risk of bronchopulmonary dysplasia among preterm infants. Amer J Perinatol 2012(EFirst). NICUs that were over 400m altitude had more babies with BPD after correcting for all the usual things than NICUs at less than 400m. I think the reliance on diagnosing BPD based on oxygen need is probably the issue here: you may also need more ventilation and O2 and therefore have more lung damage to keep the saturations at usual acceptable levels during the first days of life, but you will then also need some more oxygen to keep the alveolar PO2 at the same level as if you were at sea level. Don’t know what to do about this though, we should all move to the coast.

Natalucci G, Becker J, Becher K, Bickle GM, Landolt MA, Bucher HU. Self-perceived health status and mental health outcomes in young adults born with less than 1000 g. Acta Paediatrica. 2012 As Annie (Janvier) has said many times, we have thousands of publications detailing how screwed up preterm infants are (that is literally tue, there are thousands). In contrast very few studies of how to help them. This balance has changed in many fields, but not yet in neonatology. In contrast there is a growing recognition that most preterm infants turn out just fine! It is easier to write a paper saying that the proportions of preterm infants who have problems is increased by X%, but to recognize that most are functioning at a very acceptable to very high level is harder for people to state. The first sentence of the conclusions of this paper does have that balance, it starts, ‘Health status and mental health of former ELBW adults were overall satisfying. ‘

A similar comment starts ‘what does this mean’ section of the editorial by Michael Msall recently published in Acta. ‘First, the large majority of ELBW survivors (83%) are free of
neurosensory disability. Thus, unprecedented survival without major neurosensory disability can be expected.’ the editorial was commenting on the paper from Maureen Hack’s group, Litt JS, Taylor HG, Margevicius S, Schluchter M, Andreias L, Hack M: Academic achievement of adolescents born with extremely low birth weight. Acta Paediatrica 2012 which detailed the intellectual outcomes of 14 year olds who were babies born at less than 1 kg, that study noted yet again the specific difficulties with mathematics that are more frequent among former extremely preterm infants. They note that such infants might well benefit from specific interventions to improve these skills, but they don’t give any reference to such a program. It is about time we found ways to improve these outcomes, which are already very good, to further benefit our tiniest patients.